PT  - JOURNAL ARTICLE
AU  - Cecilia Renzulli
AU  - Mike Nash
AU  - Mark Wright
AU  - Steven Thomas
AU  - Stefano Zamuner
AU  - Mario Pellegatti
AU  - Paolo Bettica
AU  - Gary Boyle
TI  - Disposition and Metabolism of [<sup>14</sup>C]SB-649868, an Orexin 1 and 2 Receptor Antagonist, in Humans
AID  - 10.1124/dmd.110.035386
DP  - 2011 Feb 01
TA  - Drug Metabolism and Disposition
PG  - 215--227
VI  - 39
IP  - 2
4099  - http://dmd.aspetjournals.org/content/39/2/215.short
4100  - http://dmd.aspetjournals.org/content/39/2/215.full
SO  - Drug Metab Dispos2011 Feb 01; 39
AB  - N-[[(2S)-1-[[5-(4-fluorophenyl)-2-methyl-4-thiazolyl]carbonyl]-2-piperidinyl]methyl]-4-benzofurancarboxamide (SB-649868) is a novel orexin 1 and 2 receptor antagonist under development for insomnia treatment. The disposition of [14C]SB-649868 was determined in eight healthy male subjects using an open-label study design after a single oral dose of 30 mg. Blood, urine, and feces were collected at frequent intervals after dosing, and samples were analyzed by high-performance liquid chromatography-mass spectrometry coupled with off-line radiodetection for metabolite profiling and characterization. NMR spectroscopy was also used to further characterize certain metabolites. Elimination of drug-related material was almost complete over a 9-day period, occurring principally via the feces (79%), whereas urinary excretion accounted only for 12% of total radioactivity. Mean apparent half-life (t1/2) of plasma radioactivity was notably longer (39.3 h), with respect to that of unchanged SB-649868 (4.8 h), suggesting the presence of more slowly cleared metabolites. SB-649868 and an unusual hemiaminal metabolite, M98 (2-[((2S)-1-{[5-(4-fluorophenyl)-2-methyl-1,3-thiazol-4-yl]carbonyl}-2-piperidinyl)methyl]-3,5-dihydroxy-3,4-dihydro-1(2H)-isoquinolinone; GSK2329163), resulting from oxidation of the benzofuran ring and subsequent rearrangement, were the principal circulating components in plasma extracts. Two additional minor metabolites were also observed: a benzofuran ring-opened carboxylic acid M25 ([2-({[((2S)-1-{[5-(4-fluorophenyl)-2-methyl-1,3-thiazol-4-yl]carbonyl}-2-piperidinyl)methyl]amino}carbonyl)-6-hydroxyphenyl]acetic acid; GSK2329158) and an amine metabolite (M8). SB-649868 was extensively metabolized, and only negligible amounts were excreted unchanged. The principal route of metabolism was via oxidation of the benzofuran ring with the resultant M25 being the principal metabolite in excreta, representing at least 12% of the administered dose across urine and feces.